UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON , D.C. 20460

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION
September 2 2, 20 15


### MEMORANDUM SUBJECT: PC Code: 711358; Trans-1-3, 3, 3-tetrafluoropropene ; Human Health Ri s k Assessment and Ecological Effects As s e s sment to Support Proposed Exemption from the Requirement of a To lerance When Used as Inert Ingredients in Pesticide Fonn ulati ons.


### All PC Code: 71 1 358 

### D ec i s ion No. : N/A DP Barcode: N/A Regul a to ry Action: Inert To lerance Exemption; 40 CFR 18 0.910 , 180.930 and 180.940 (a) 

### Petition No: IN-10753 All CAS Reg. No: 29118- 24-9 

### Inert Tracking No: N/A
FROM:

Through:

TO: Lisa Austin , Ph.D., Toxicologist Mark Dow, Ph.D. , Biol ogist Chemistry , In ert and To xic rt logy Assessment Branch ( CITAB) Registration Division (750 ) 

# J
Kerry L e if e r, T ean1 Leader



# :rJ.~ 

# ..._

**~** C hemi stry , Inert and



## Toxico

**~J y**  **A~esessment** Branch (CI T A B ) Registration Division (7505P ) PV Shah , Chief Chemistry , Inert and Toxicology Assess ment Branch (C ITAB) Registration Di v i sion (7505P)EXECUT IVE SUMMARY EPA received a petition (P P # 1E7938) from The Acta Group , L.L.C. , 2000 Pennsylvania Avenue, N.W., Suite IOOW Washington , D.C. 20037 , on behalfofHoneywell Specialty Materials N IC4 , I 01 Columbia Road , Morristown, NJ 07962-1053 requ es ting an exe mption from the requirement of a tolerance for the use of trans 1- 3, 3, 3-tetrafl uoropropene (CAS Reg. No. 29 118- 24-9) as an inert ingredient (propellant) up to 30% in pestic ide products on all pre- and post-harvest food commodities under 40 CFR part 180.910 ; in pesticide product s applied to animals under 40 CFR part 180.930 ; and in pesticide products used for food

- contact surface sanitiz in g solutions under 40 CFR part 1 80.940(a). E PA published the notice of filing (NO F) for this petition in the Federal Register on April 4 , 2012 (77 FR 43566). No comments were received in respon se to this notice. Currently, tran s 1-3 , 3 , 3- tetrafluoropropene is recommended for approval as an aeroso l prope ll ant under th e Significant New Alternatives Policy (SNAP) as an alternative for o zo ne-depleting substances

. Toxicit y summaries oftrans 1-3, 3, 3-tetrafluoropropene were reproduced from data submitted by The Acta Group , L.L.C. , on be ha lf of Honeywell Specialty Materials NIC4. Trans 1-3 , 3 , 3-tetrafluoropropene was administered via the inhalation route of exposure only in these stu dies. So me of the s tudies contained the incorrect chemica l name but contained the corr ec t alternate CAS# 1645-83-6. Therefore , in the some of the fo ll owing studies, tran s 1- 3, 3, 3- tetrafluoropropene was identified by the alternate CAS # 1645-83-6 when the incorrect name was used. Acute inh alation toxicity was low for CAS # 1645-83

- 6. Ac ute inha lat ion LD so s we re 

### 2: I 01,850 parts per million (ppm) (approximately 713 milligrams/kilogram ( mg/kg)) in rat s and mice. CAS # 1645-8 3 -6 was not a dermal irritant in rabbits. Two subchronic toxic ity stud i es via th e inhalation route of exposure were ava ilabl e for CAS# 1645-83-6 in rode nt s. Toxicit y was not observed in rats or mice at doses as high as 5000 ppm (approximately equi valent to 7800 mg/kg/ day human equivalent dose) following 13 weeks and 90 days of exposure , respectively. Th e 90 day inha lation toxicity study in mic e a lso evaluated the carcinogenic potential of CAS # 1645-83-6 by conducting a toxicog e nomic assessment. CAS# 1645-83-6 was classified as non-carc inogeni c by the toxicogenomic assessment at I0,000 ppm (approximately e quivalent to 15600 mglkg/day human equivalent dose), the highest do se tested

. De ve lopmental toxicity studies via the inhalation route were available in rats and rabbits. Neither maternal nor developmental toxicity was observed in either study up to 15000 ppm (app r ox im ately equ ivalent to 23400 m g/kg/ day human equivalent dose) , the high es t dose tested. Two Ames Te s t s via gas exposure were available for review with CAS# 1645-83-6. Th e mouse micronuc le u s assay was performed via inhalation exposure . These tests we r e negat ive. A chronic study with CAS # 1645-8 3 -6 was not available for review. A chronic study with trans-1 , 3,3,3 -tetraflu oropropene is not availab l e for review. Although a chronic toxicity study is not avai labl e, there is no concern for the lack of it b e cause toxicity is not see n following up to 13 weeks of exposure to trans-1.3.3 , 3-tetrafluoroprop-1-ene at excess ive d oses (7 800 and 15 , 600 2mg/kg/ day). Also, toxicity is not seen in the developmental study at an excessive dose of23 ,400 mg/kg/day. Therefore , the likelihood that chronic exposure to doses below the limit dose will result in toxic effects is highl y unlikely and the Agency has no concerned with regard to 

### it. Neurotox ic ity studies were not available for review. However , evidence of neurotoxicity was not observed in the submitted inhalation studies. Immunotoxicity s tudies were not available for review. However , very slight mononuclear cell infiltrates in the heart were observed in only females (3 / 5) at the LOAEL

**of 5000**  ppm (approx imatel y equiva l e nt to 7800 mg/kg/day human equivalent dose lowest dose tested) following 10 days of exposure via inhalation in Sprag ue Dawley rats. This effect was not dose dependent with regard to either incidence or severity. Simi lar effects along with increased monocyte count were observed in the heart at 15 , 000 ppm (approximately equivalent to 23400 mg/kg/day human equ iva lent dose; highest dose tested) in a 13 week study via inhalation in Sprague Dawley rats. The NOAEL was 5000 ppm (equivalent to 7800 mg/kg/day human equivalent dose). This st udy included more rat s, was conducted in the same species ofrats that underwent the same route of exposure and was of longer duration (13 weeks vs I 0 days). Mononuclear cell infiltrates in the heart were not observed at 5000 ppm (equivalent to 7800 mg/kg/day human equivalent dose) in either the male or female rat as was observed in the I 0 day study. Th erefore, since the incidence and severity of these effects were not dose-dependent in the 10 day study, the 13 week s tud y was considered more reflective of toxicity resulting from exposure to CAS# 1645-83-6. Howev er, the Agency is not concern about thes e effects si nce the y occur well a bov e the limit dose and exposure beyond that is highly unlikely and unrealistic. Two studies were availabl e for CAS # 1645-8 3-6 on male rod en t metabolism and pharmacokinetics. In rodents , CAS# 1645-83-6 via the inhalation route of exposure was rapidly absorbed, metabolized and excreted. The urine was the major route of excretion. In rats, the major metabolite was S

- (333 -trifluoro-trans-propenyl)-mercaptolactic acid. In mic e, the major metabolite was a presumed amino acid conjugate of 3 , 3 , 3-trifluoropropionic acid. Other identified metabolites were S-(3.3 , 3-trifluoro -transpropenyl)- L-cysteine , N-acetyl-S-(3,3 , 3- trifluoro-trans-propenyl)-L-cysteine and 3,3,3-trifluoropropionic ac id. An endpoint of concern was not identified in the toxicity database for trans 1-3 , 3, 3- tetrafluoropropene. No adverse effects were observed at doses as high as 5000 ppm (approximately 7800 mg/kg/day hum an equivalent dose). Ther efore, a qualitative risk assessment for trans 1-3 , 3, 3 -t e trafluoropropene was conducted for all pathways of human exposure for acute and chronic dietary exposure assessment and s hort and intermediate dermal and inhalation exposures. Trans 1- 3 , 3, 3-tetrafluoropropene is expected to per s i s t in soil and sediment. Bioconcentration in aquatic organisms i s moderate to high. 

### It i s not expected to be toxic to aquatic organisms. Trans l-3 , 3 , 3 -t etrafluoroprope ne is not biodegraded by microorganisms in sludge

. Potential a r eas of environmental justice concerns, to the extent possible. were considered in this human health risk assessment, in accordance with U .S. Executive Order 12898 , "Federal Actions to Address Environmental Justice in Minority Population s and Low-Income Populations ," http: // www.eh.doe.gov/ oepa/guidance / justice / eo12898.pdf. 3Taking into consideration all avai l able information on trans 1-3 , 3 , 3-tetrafluoropropene , EPA conc ludes that there is a r easonab le certainty that no harm will result to the general population or to infants and c hildren from aggregate exposure to trans 1-3 , 3 , 3- tetrafluoropropene. Therefore , the establishment of an exemption from tolerance under 40 C FR 180.910 , 180.930 and l80.940 (a) for residues of trans 1

- 3, 3 , 3- tetraflu o ropropen e when used as an inert ingredient (propellant) at no more than 30% by weight in the end-product formulation can be considered safe under section 408 of the FFOCA.


### 1. 

### B AC KGRO UN D On November 3 , 20 11 The Acta Group , L.L.C. , 2000 Pennsylvania Aven ue , N.W

. , S uite I OOW Washington , D.C. 20037 , on beha lf of Honeywell Specialty Materials NIC4 101 Co lumb ia Road , Morr i stown , NJ 07962-1053 , submitted a petition ( PP# I E7938) requesting an amendment to 40 CFR 180.910 , 180.930 and 180.940 by establishing an exempt ion from the req uirement of a tolerance for residues of trans 1-3 , 3 , 3-tetrafluoropropene (CAS R eg . No. 291 I 8-24-9) , when u se d as an inert ingredient as a propellant in pesticide formulations

. E PA published the No tic e of Fi ling for this pet iti on in th e Federal R eg ister on April 4 , 20 12 (77 FR 43566). No comments were received in response to this notice

. Currentl y, tran s 1-3 , 3 , 3-tetrafluoropropene was recomm e nded for approval as an aerosol propellant under the Significant New Altematives Policy (SNAP) as an altemative for ozonedep l eting s ub s tanc es. In the ri sk screen document fo r HFO 1234ze (trans l-3 , 3 , 3- tetrafluoropropene) ICF recommended an acceptable exposure limit of I , 000 ppm for lon g -te rm occupational exposures based on the 13-week inh a lation study in rat s. Intermittent consumer exposure was not to exceed 420 ppm based on the 4-week inhalation study in rats (E PA , 20 I 0). This document p rovides an assessment of the risk to hum an health a nd the environment for trans 1-3 , 3, 3 -tetrafluoropropene when u se d as an inert ingredient (propellant) in pesticide formulations. Study reports s ubmitted to th e Agency were reproduced and refere nced in thi s assessment.

2. In e rt In g r e dient Profile Some ofthe ph ys ical and chemical characteristics oftrans 1- , 3, 3, 3 -tetrafluoropropene along with its s tru cture and nomenclature , are found in Table I.

Table 1. Physica l a nd Chemical Prop ertie s of Trans 1-3 , 3 , 3 -tetra flu oropropene Parameter Va lu e So urce

4Structure

CAS# Molecular Weight (g/mo l ) Co mm on Names

Physica l State Meltin g Po int ( ° C) Boiling Point ( ° C)

Density (g/cm3) Va por Pressure (hP a) Partition Coe fficient (Log P) Water So lubili ty Log Kow Spec i fic Gravi ty


### 3. Hazard Asses s ment F, 

## l C H I '\, I F c-;:;C, I F H
291 18-24-9; 1645-83-6 114 ! -Pr ope n e , 1 ,3 , 3 , 3 -tetrafluo ro - , (I E)- , HF0-1 234ze, (E)- 1.3 , 3 , 3-tetraflu orop r op- 1- ene

Clear co lorl ess liquifi e d gas Not Availab le -1 9 No t Ava il ab le 4 192



### 1.6 373 mg/ L 2.0 1 Not Ava il able Younis (2006)

Spruit et.al. (2006) Ho ri (2008) MRID 48649503 Sprui t et.a l. (2006) Kayashima (2008 ) MRID 48649504 Spru it et.al. (2006) Hori (2008) MRID 48649503 Spruit e t. al. (2006) S pruit et.a l. (2006)

T he following toxi c it y studies for tr an s 1-3 , 3 , 3 -tetra fluoropr o pene we re repr oduced from the data package s ubmitt ed by Th e Acta G roup , L.L.C., on behalf of Honeywell Spec ialty Mate rial s N IC4. In some of the s tudie s the chemical nam e was in co rrect but was co rrect ly identified by the altern ate CAS # 1 645-83-6

. Therefore , in th e fo ll ow in g studies. tran s 1-3 , 3 , 3

- tetrafluoropropene was identified by the alternate CAS # 1645

- 83-6 w hen the incorrect name was u se d. Acute Toxicitv S tudie s



### Tab le 2

. Acute Toxicity Profile of CAS Reg. No.# 1645-83-6 Study Type Reference Result s Acu t e Dermal DiD onato, 20 1 0 Not an irritant Irritation- rabbi t
5

### Table 2. Acute Toxicity Proftle of CAS Reg. No.# 1645-83-6 St udy Type Reference Results Acute Inhalation

- Hof fm a n , 2004 L Cso> 10 1 , 850 m g/ L ;(a ppro x im a tel y 713 mous e mg/k g/day) Ac ute Inhalati o n- LCso > I 03 ,3 00 mg/L ; rat (app ro x im ate ly 723 mg/ kg/ day) Acute Inhalation

- Hoffman , 2010 Negative for micronucleu s assay Micronucleus As say -mou se

D erma l Irri tation : In an acute dermal toxicity stud y , 3 rabbits ( I male ; 2 fema l es) we r e dosed with 0.4 ml of trans 1-3 , 3, 3- t etrafluorop ropene onto a hilltop chamber for a 4 hour exposure . Th e male a nim al was dosed on Si t e #2 a nd th e two female animals were dose d on S ite # 3

. E ryth e m a and e d e m a were sco r ed at 60 minutes , and at 24 , 48 and 72 hours following patch remo val. An imal s we re observed for toxicolo g i cal and pharmaco logica l effects at each dermal observation period and observed for mo11alit y dail y. Body weig hts of a ll animals were reco rded pretest and te m1in ati o n. Ne ither Erythema nor edema was observed a t any time point following the 4 hour exposure. Th e re were no a bnorm a l phy sica l s ig n s a nd b o d y weight changes were normal. CAS# 164 5- 8 3-6 was not a dermal irritant (MR JD 486495 I 0).

Inhalation: A n acute inh a lati on toxicity range-fi ndin g s tud y was co nducted in CD -I mic e (2 / sex) at 20 , 000 or 100 ,000 ppm (a pproximately 140 o r 700 m g/ kg/day) of CAS # 1645-83- 6. The t est substance was ad mini s tered via who le-bo d y exposure for 4 ho urs. Exposure level s were dete rmined u s in g a M lRAN® A mbi e nt Ai r Analyzer. Observations for signs of toxicity we r e conducted o n all animals at fifteen

- minute intervals durin g th e first hour of ex po s ure and hourly for th e rem ainder of th e exposure . D e tail e d physical observat ion s were performed on all animals just p ri or to exposure and imme diatel y upon removal from the chamber and once daily thereafter. Body weigh t m easure m e nt s were obtained just prior to ex posure and at termination. A fter a 7 -d ay p ost
- exposure observa ti on period , a ll animals wer e sac rificed. Complete macroscopic postm ortem examin ations were p e rformed o n all animals

.

6There were no mortalities or treatm e nt relate d effects on bod y weight. At 20,000 ppm (app ro x imatel y 140 m g/kg/ da y) , l abored breathing was observed during the last 2 hours of exposure in 2/ 8 animals. At I 00 , 000 ppm ( app rox imate ly 700 mglkg/day) , 4/ 8 animals displayed labored breathing during the la s t 2 hour s of exposure. The LCso was greater than I 0 I ,850 ppm ((app roximate ly 713 mg/kg/day) bas ed on th e average analytical co ncentr at ion ) (M RlD 48649512). Acute Inhalati o n and Micronuc le us Assay: Five mal e and 5 female Sprague Dawley rat s were exposed (nose only) to 0 (contro l ) , 100 , 000 or 207 , 000 ppm (approximately 700 or I449 m glkg/ day) of CAS # 1645-83-6 for 4- hours and held for a 14-day post-exposure observation period. A ll rats survived and there we re no t ox icolo g ically significant findings. Additionally, groups of I 0 male and 10 f e male CD-I mic e were expose d to the same leve ls. Mice were held for 1 or 2 days following exposure and then euthanized and bone marrow san1pled for micronucleus evaluation. There were no toxic o logicall y significant signs reporte d and th e re was no increa se in the frequency of micronuclei. There w ere no mortalities in the mous e study. The LCso was g reater than 10 3 , 300 ppm (app r ox imate ly 721 rng/kg/day). Micronucleus evaluation: No st ati st ica ll y sign ificant increases in the frequency of rnicronucleated polychromatic erythrocytes and no substant ia l decrea ses in the proport ion of polychromat ic erythrocytes were observed in mic e exposed to CAS# 1645-83-6 and killed 24 or 48 hour s later , compared to concurrent negative con trol va lu es (P> O.O I in each case). Th e positive control compound , cyclophosphamide, produced hi g h ly sign i ficant increa ses in the fre q uency of micronuc leated polychromatic erythrocytes at 24 and 48 hours afte r dosing (P < O.OO I )

. A stati stically sign i ftc ant decrease in the proportion of polychromatic eryth r ocytes was observe d at th e 48 hour sampling t ime o nly (P > O.O 1 )

. lt was conc l uded that CAS # 1645-8 3 -6 d id not show any evidence of causing an in cre ase in micronuclei or bone marrow cell tox icit y whe n administered to CD-I mice for a sing le 4-hour nose - o nl y inhalati on ex po s ure in thi s in v ivo test procedu re (M RID 48649516).


### R ep ea t ed D ose S tudi es vi a Inhalation: In the following studies , the d oses in the parentheses represent th e ap pro xi mate hum an equivalent do se in m g/kg/day that wa s calcu lated by the rev iewe r. The formula used to d e rive th ese value s can be found in the appendix. 2-week toxicity -Rat: Groups of 5 mal e and 5 female Sprague Daw ley rats we re exposed nose -onl y t o target concentrations of 0 (control) , 5,000, 20 ,000, or 5 0 , 000 ppm (7800 , 3 1200. or 780000 mg/kg/day)

7CAS # I 645-83-6 for 6 hours a day, 5 days a week during a 2 -week period , with a total number of 10 exposure days. Data on clinical observations, body weight gain, food consumption, food convers ion efficiency, he matology and cl ini cal chemistry were determined. I n addition , animals were examined grossly at necropsy, o rgans were weighed , and a selection of organs and tissues (including the complete respiratory tract and na sa l passages) was examined micro sco pically. The mean actual concentrations( ± standard deviation) of CAS# 1645-83-6 in th e test atmospheres , based on total carbon analysis, were 4,961 (± 52), 20 , 904 (±833) and 51,770 (±1778) ppm (7739, 32610, or 80761 mg/kg/day) for the low- , mid- and high-con cent rati on levels. Corresponding nominal concentrations as calculated from the ratio of the fl ow of test material and the total flow were 4,895 , 2 0 ,4 62 and 49,186 ppm (7636, 31921 and 76730 mg/kg/day). Daily observation of the animals did not rev ea l any exposure- r elated c lini cal abnormalities. No treatment-related differences in body weight gain, food consumption and food conversion effici ency were seen. The concentration of red blood cells (5%) and thrombocytes (12%) were increased and the mean corpuscular hemoglobin concentration was decreased (2%) in mal es of the high concentration group. Prothrombin time was increased in fema le anima ls of the mid- (22%) and high (24%) concentration groups. Monocyte count was increa sed (100%) in the male animals of the high concentration group. The levels in plasma of glucose (52%), alanine aminotransferase (45%), aspartate aminotransferase (115%), albumin (7%) and urea (53%) were incr eased and the levels of cholestero l (53%) and phospho lipid s (28%) and so dium (2%) were decrea se d in male animals of the high

- concentration group . The lev e l s of aspartate aminotransferase (56%) and urea (26%) wer e also incr eased in the male ani mal s of the mid concentration group. In female animals of the high concentration group, the leve l s of a lkaline phosphatase (39%), alanine aminotransferase (50%) and urea (53%) were increased and cholesterol was decreased (53%). In the female animals of the mid concentration group th e level of cholesterol ( 17 %) was also decreased and the level of aspartate aminotransferase was increased (50%). Although the latter was also higher (31 %) in female animals of the high concentration group , it did not reach s tatistical s ignifi cance. Absolute ( 1 3%) and relativ e lung (9%) weights were decreased in male anima ls of the high concentration gro up. Abso lute (9 and 13%) and relative ( 1 3 %) liv er weights were increased in male and female animals of the high

- concentration group , though statistic al significance was not reached for the abso lute liver weight ( 13%) in the female anima ls. Macroscopic examination at necropsy re vealed an exposure-related pale appearance (4/ 5 vs 0 in control an imals) of the li vers of almo st all an im als of the high-concentrat ion group. Microscopic examination revealed exposure-related h i stopat hological changes in the liver of the mid- and high concentration male (mononuclear ce ll agg r egates/ necrotic hepatocyte s and
8hepatocellular vacuo lation) and high concentration femal e (increased severity of h e patoc e llul ar vacuolation) animals, in the na sa l pas sages ( decrease d go blet cell expre ssion 

### in the septum) of the hig h-co ncent rati on male and femal e anim als, and in the heart (very s li g ht m o nonuclear cell infiltrates) of th e mid- and high -c oncentration male and f e male animals. The NOA EL was not estab li shed. T he LOAEL wa s 5,000 ppm ( approx imatel y 7800 m g/kg/ d ay) based o n mononuclear ce ll infiltrates in the heart of female animals (M RID 48649515).
1 3

- week toxicity

- R at: G roups of I 0 mal e and I 0 fema l e Spragu e D aw le y rats were ex p osed nose - on ly to target concentrations of 0 (cont rol ) 1500, 5,000 ppm or 15 ,000 ppm (mean actual concentra tion s(± standard deviation , ba se d on total carbon analy s is, were 1504 (± 4 ), 4999 ( ± 18) , and 15 , 00 2 (± 57) ppm (app rox im at ely 2340. 7800 and 3 12 00 mg/kg/day) CAS # 1645-83-6 (gas) for 6 hours a day , 5 days a week during a 13-week period , w ith a tota l number of 63

- 64 ex po su r e days. Clinical signs , body weig ht gai n , food consumption, food conve rs ion efficiency , ophtha lmoscopy , h e matology and clinical chemistry we re evaluated. In addition , an imal s were exami n ed grossly at nec ropsy, organs were weighed , and a se lec tion of organs and tissues (inc ludin g the comp le t e respiratory tra c t and na s al pas sages) wa s exam in e d micro sco picall y . One female control animal was found dead o n the 75th day of the study

. Otherw i se, th ere were no mortalities. There w e r e no treatm e nt-re lated find ing s re gardin g c lini cal abnormali t ies, body weight gai n , food consumption. food co nve r si o n effic ienc y . or op hth a lmo scop ic exami nation

. T h ere were s i g nifi ca nt di ffe re nc es see n in hematology parameters , i.e. incre ases in thrombocytes ( 14 %) and monocytes ( 100%) in m a le animals of the high co ncentrat i o n g ro up and incr eases in he moglobin conc e ntrati o n (4%) , and packed cell volume (6%) , and to a s li g ht ex tent also monocytes (92%) in females of th e high co ncentrat ion group may be related to the treatment. S imilarl y , there were s i g nifi cant in creases seen in clinical chemistry parameters, i.e. in ASA T ( 129%) and urea ( 14 %) in pla s ma ofthe mal e animals of the hi g h co nce ntr ation gro up , and in g luc ose (18%) , urea (22%), in o rganic phosphate (20%) , and pota ss ium ( II %) in female an im als of the high conce ntrat io n g roup. T he abso lute and re lativ e weight of th e uteru s was d ec rea se d in female animal s of the hi gh concentration gro up. This findin g was cons id ered due t o uterus weig ht variation s re lated to the oestrous cycle r ather th a n re la t ed to the ex po s ure. No othe r changes in absolute o r re lati ve organ w e ights were detected

. Mac roscopi c examination did not s how exposure-related gross path o logy. Mic ro scop ic examination revealed that CAS # 1 645-83-6 induced multifocal mononuclear cell infiltrates in the hea rt of the high- co ncentration m a les (9/ 1 0) and females (5/1 0) ve rs u s 0/ 1 0 in contro l animals. Fibros is was not observed.

9The NOAEL was 5000 ppm (7 800 mg/kg/day). The LOAEL was 15000 ppm (23400 mglkg/day) based on increased monocytes, potassium and increased incidence of multi focal mononuclear cell infiltrates in the heart of the high-concentration males and females (MRJD 48649517). Developmental/Reproduction Toxicity Stud ies: Range Finding- rabbit Four g roups oftime-mated female New Zealand White rabbits (6/group) were exposed to either clean filt ered air or vapo r atmospheres of test art icle , CAS# 1645 -8 3-6, for 6 hours daily in whole body inhalation chambers durin g gestation days 6

- 28. Target test article concentrations were 0, 1500 , 5000 and 15000 ppm (2340, 7800 and 23400 mglkg/day). Overall mean measured exposure concentrations were 0 , 1502, 5026 and 15040 ppm (ap pr oxima tel y 2340, 7800 and 23400 mg/kg/day) for th e same respective target exposures. All animals were observed twice daily for mortality and moribundity. Cl inical observat ions , body weights and food consumption were reco rded at appropriate interva ls . On gestation day 29 , a lapar o hyster ecto my was performed on eac h female. The uteri , placentae and ovaries were examined. and the numbers of fetuses , early and late resorptions , total implantations and corpora lutea were recorded. Gravid uterine weights were recorded , and net body weights and net body weight changes were calculated. The fetuses were weighed and examined for external malformations and developmental variations. All anima l s surv ived to the sc hedul ed ne cropsy on gestat ion day 29

. No clinical observation s or macro sco pic findings were attributed to test article exposure. Mean maternal body weights, body weight gains , net body weights. net body weight gain s, gravid uterine weig ht s and food consumption were una ffected by test article exposure at all exposure levels. Intrauterine growth and survival were unaffected by maternal test article exposure at 1500 , 5000 and 15000 ppm (2340, 7800 and 23400 mg/ kg/day). No external fetal malformations were attributed to mat erna l test artic le exposure; no external d eve lopme ntal variation s were noted for fetuses at any exposure lev el. The maternal and developmental NOAEL was 15000 ppm (23400 mg/kg/ day) (MRI D 48649514). In another study, 88 (22 do es/ dose ) time-mated female New Zeala nd White rabbits received who le-b ody inhalation expos ures with clean air (ai r co ntrol ) o r with CAS# 1645-83-6 at exposure concentrations of 4,000, 10 ,000 or 15,000 ppm (6240, 15600 and 23400 mglkg/ day) from GD 6 to GD 28 (G O 0 =day of mating confirmation). The exposure durations were 6 hours per day for 7 consecutive days per week

. All animals we re euthanized and necropsied on GO 29. Viability, clinical observations , bod y weights and feed consumption were evaluated. A macroscopic po s tmortem evaluation was performed on GO 29 , during which corpora lutea, implantation data and uterine weights were 10recorded. The fetuses were removed , weighed (live and rec entl y dead fetuses), sexed and examined externally for defects. All fetuses were exami ned for soft tissue abnormalities , skeletal abnorma liti es and ossification state. Placenta s were exa min e d and weighed. There were no effects of exposures o n survival, c linical signs, body weights, food consumption or maternal or fetal findings at sac rific e. The maternal and developmental noobserved-adverse- effect levels (N O AELs) were 1 5 , 000 ppm (23400 mg/kg/ day) the highest dose tested (M R I D 48649519).
Twenty-four mated female W istar rats were exposed (nose only) to CAS # 1645-83-6 at concentrations of I ,500; 5,000 and 15 , 000 ppm (mean actual da il y concentrations as mea s ured by total carbon analysis , were 1 , 504 ( ± 3); 5 , 003 (±10) and 14 , 997 (± 15) ppm (equiva l ent to 2340, 7800 and 23400 mg/kg/day), respectively. The control group of twenty-four mated females was exposed to clean air. At Caesarean section females and fet u ses of all gro ups were macroscopically exam in ed

. Fetuses, place nt as and reproductive organs were weighed. Fetuses were f urth e r processed for fetopathological exa mination. There were no mort a litie s or treatment related clinical observations

. No effect was see n on the mean matern a l body weight and on food consumption. No stat i stically signifi cant differences were observed in the female fecundity index , gestation index , number of corpora lutea , the number of implantation s ites , number of liv e fetuses, post-implantation lo ss and the sex ratio

. No effect was seen on th e weight of gravid uterus, empty uterus and ovaries. Macroscopic findings at necropsy did not reveal any remarkable o r treatment related findings among the dos in g and control groups. No stati stically significant differences in th e incid ences of fetal external observations and / or placental findings were observed. F etal and placental weights we re not affected. No treatmentrelated effects were observed at visceral and skeletal examin ation. The maternal and developmental NOAELs were 15,000 ppm (23400 mglkg/day), the highest dose tested (MRT D 48649518). Dern1al Toxicity and Dermal Absorption Studies: Dermal toxicity and dermal absorption studies were not available for review. H owever, based on the physical properties of CAS # 1645 -8 3 -6 dennal expos ure is expected to be negligible. Neurotoxicity Studies: Neurotoxicity studies were not available for review. However , evidence of neurotoxicity was not observed in the submitted studies. lmmun otoxicity Study-Rat:

11lmmunot ox icity stud i es were not availabl e for rev iew. However, very s light mononuclear cell infiltrates in the heart were observed in only femal es (3 / 5) at the LOAEL of > 5000 ppm (7800 mg/kg/day; lowest dose tested) following I 0 days of exposure via inhalation in Sprague Dawley rat s. T his effect was not dose dependent with regard to e ither incidence or severity. Monocyte count was increa sed and multifocal mononuclear cell infilt rates were also observed in the heart at 15 , 000 ppm (23400 mg/kg/day; highest dose tested) in a 13 week study via inhalation in Sprague Dawley rats. The NOAEL was 5000 ppm (equivalent to 7800 mg/kg/day). This study included more rats, was conducted in the same species of rats that underwent the same route of exposure and was of longer duration (13 weeks vs 10 days). Mononuclear cell infiltrates in the heart were not observed at 5000 ppm (7800 mg/kg/day) in e ither the male or female rat. Since the incidence and severity of mononuclear cell infiltrate s in the heart were not dosedependent 

### in the 1 0 day study , the 13 week study was considered more reflective of toxicity r esult ing from expos ure to CAS# 1645-83-6. However, the Agency is not concern about these effects s inc e they occur well above the limit dose and exposure beyond that is highly unlikely and unrealistic. Mutagenicity: Ames Test Trans 1-3 , 3, 3-tetrafluoropropene was tested at 50000 ppm (7800 0 mg/kg/ day) in 

### Salmonella typhimurium strain s TA98, TA I 00 , TA 1535 and/or TA 1537 in an Ames Test. No substantial increases in revertant colony numbers of any of the tester strains were observed following treatment with CAS # 29 118- 24-9 at 50000 ppm (78000 mg/kg/ day) , in th e presence or absence of S-9 mix , in either mutation test. T he concurrent po s iti ve controls demonstrated the sen s itivity of the assay and the metabolizing activity of the li ver preparations. It appeared that the dose level of ethylene oxide was slightly too high in the first mutation test as toxic ity was observed. H owever th e toxicity and positive response observed w ith WP2 vwrA in the presence of S-9 mix demonstrated that the bacteria on the seeded plates were exposed to the gas in the desiccator. A satisfactory positive r es pons e was obtained with ethyl ene ox ide in the second mutation test. The study was negative for mutagenicity (MR ID 48649521). The mutagenicity of CAS # 1 645-83-6 in bacteria u s ing 

### Salmonella typhimurium (S. typhimurium) TA98 , TA I 00 , TA 15 35 , TA1537. and Escherichia coli (E. coli) WP2uvrA/pKMI01 2) , by the gas exposure method with ( + S9mix) or without (

- S9mix) metabolic activation

. Th e test was performed with 0, 1 % , 2%, 2, 5%, 10% , 20% and 50% (app roximately 0 , I 0000 , 20000 , 25000 , 100000 , 200000, and 500000 ppm) of CAS # 1645-83-6. The te s t substance did not increase in number of revertant co l on ies more than twice of that of the negative contro l in any s train w ith or without metabolic acti vation , and did not inhibit bacteri a l g ro wth i n any condition of the test. The numbers of revertant colonies for the negative and positive controls were within the range of standard values derived from historical control data. B ased on the above resu lts, CAS # 164 5-83

- 6 was assessed to be no n-mutage nic (negati ve) in the reverse mutation test in bacteria (MR ID 48649522).
Chronic/ Carcinogenicity

- Rat: 12(90-day s tud y evaluated for carcinoge ni c potential using ge ne exp res s ion) Female B6 C3F l / Crl mice and mal e F 344 / C rlBR rats ( 10 / dose) we re expose d for 13 weeks to H F0 -1 234ze

. Known carcinogens were included in the study as p os itive co ntrol s . Tetrafluoroethylene , 1-Amino- 2, 4-dibromoanthraquinone , Tris (2 ,3 -dibromoprop y l)pho sp hate I , 5

- are known mo u se li ve r and rat kidn ey carcinogens. Only the kidney and li ver we re eva lu ated ba se d on the sensit ivity of each s pecie s to the formation of tumo r s in these o rgans. The animals w ere exposed to 0 , 2000 or 10 , 000 ppm (3 120 and 1 5600 m g/kg/ day) ofCAS # 1 645 -83- 6 six hour /day / 5 days/ week for 13 weeks in s in gle whole body chambers. Following a s ubchro ni c exposure , c han ges in gene expr ess ion biomarkers we re used to ass ess the carcinogenic pote ntial of CAS # 1645-8 3 -6. A predictive set of gene s wer e identified and a lo ng w ith the supp o rt vec tor mac hin e (SV M ) model was u sed to pr e dict th e carcinogenic potenti a l of CAS# 1645-83-6. T he re were no trea tment-relate d mortalities in either s tudy. In rat s, bodyweight , kidney and li ver a bso lut e and relative we i ghts we re comparab le to controls , there were no treatment r e lated hi sto pathological lesi ons. Base d on gene express i on changes and stat istica l c lassification model s, CAS# 1645 -8 3

- 6 was pr e dicted to be non - carci no genic in the mal e rat kidney and female mo use liver (MRTD 48649520).
Me taboli s m-Rat: Male Sp ra g u e - Dawl ey rat s we re exposed t o air containing 2, 000 ; I 0 , 000; or 50 , 000 ppm (3 120 , 15600 and 78000 mg/kg/ day) (n 

## = 5 /concentration) HF0-1 234ze

. Male B 6C3F l mice we re only exp osed to 50 , 000 ppm (78000 mg/kg/day) HF0-1234ze. All inhalation exposures were conducted for 6 h in a dynamic exposure chamber. In urine samples of rats exposed t o 50,000 ppm ( 78000 m g/kg/ day) HF 0-1234ze , the pr edo min ant metabolite was S-(333-trifluorotran s -pr ope n y l) -mercapto lactic ac id and accounted for 66% of all integrated 19F-NM R signals in urines. No 19F-NMR sig nals w ere found in s pect ra of rat urine san1p les collected a fter inh a lati on expos ure to 2000 o r I 0 , 000 ppm (3 1 20 o r 15600 m g/ kg/ day) HF0 -1234ze like ly due to in suffic i e nt s en s itivity. S

- ( 3 ,3,3- Trifluoro-transpropeny l )

- L-cysteine, N

- accty l- S -(3 ,3,3

- tritluoro-trans-propeny l ) -L-cy ste ine and 3,3 ,3 -trifluor o propi o nic acid were a lso present as metabolites in urine samples of rats and mic e . A pr es umed a min o ac id c on jugate of 3,3,3

- tr ifluoropr opionic acid was the major metabolite ofHF0-12 3 4 ze in urine sample s of mic e exposed to 50 , 000 ppm (78000 mg/ kg/ day) and related to 18 % of tot a l integrated 1 9 F-NMR signals. Quantification of thr ee metab o lit es in urin es o frat s and mi ce was pe rform e d , u si ng LC/ MS-MS and GC/M S. The quantifi e d amounts of th e metabolite s exc reted with urin e in both mice and rats, sugges t on ly a low ex t e nt (< 1 % of dose received) of biotransfonnation ofHF0

- 12 3 4ze and 95 % of all m e tabolites were excreted wi thin 18 h after th e e nd oft he ex posur es (M RID 48649524 )

. Acute Cardiac se n s iti za tion Study-Spe c ial Stud y - Do g: HF0-1234ze was adminis t e r

e d to 6 male dogs via mu zz l e -only inhalation expo s ure (va por) as ac ute ex posures at concentrations of2 .0 %
. 6.0% and 12 % (2 0 , 000 , 60 , 000 and 120 , 000 ppm ; and eq ui va lent to 3 1200 , 93600 and 187200 mg/kg/d ay)

. Each do g serve d as its o wn control. Animal s were administ e re d a pr e -expo s ure d ose of epinephrine as a bo lu s injection v ia a cephalic 13vein approximately 5 minutes prior to exposure to the te s t articl e . Five minutes after exposure to th e test article began , the anima ls were administered a challenge dose of ep inephrine. F o ll owi n g the fina l exposure , all dogs we re r e turn ed to stock. All anima l s we r e observed twice d aily fo r mortality and moribundity. C linical exami n at io n s were perform ed prior to initiation of eac h exposure, continually during th e expo s ure and immediate ly foll ow ing each e xpo sure period. Detai le d phy s ical exami nation s were performed and body we ight s w ere collected on the day prior to the first day of e xposures and at the completion of all exposures . Electroca rdio g raphic data were reco rded c o ntinuou s ly throughout the pre - exposure epinephrine dosing , ex po s ure to the test gas and for 5 minutes fo ll owi n g adminis tration of the challenge epi ne phrin e dose ( t o tal of approx imately 17 minutes ). All anim als survived to study termination. T here were no tes t art icl e-relate d clinical observations. Body weights were unaff ec ted by test article administration

. There was no indic ation of car d iac se nsiti zati o n noted in an y dogs at 20,000, 60,000 or 120,000 ppm (3 1200, 93600 an d 187200 m glkg/day) HF0-1234ze whe n fol lowed by the administration of epinephrine. The no- o bserved- eff ect l eve l (NOEL) for HF0-1 234ze was 120 ,000 ppm ( approx im ate ly 187 2 00 mglkg/day hum a n equ iva le nt dose) , the hi ghest dose te s t e d for cardiac sensi ti zati on (MRI D 48649523).



### Table 3. Toxicology Proftle for Trans-1, 1, 1, 3 - tetrafluoropropene Study Type Doses Results 2 week -I nh alation 0, 5,0 00 ; 20,000; or 50.000 NOAEL was not established. Tox i c i

ty-Rat ppm (equivalent to 7800, LOAEL = 5000 ppm (7800 m glkglday) was based on 31200,or780000 m

glk gl

day) m o nonucl ear ce ll infiltrates in th e h eart of female animals. 13 week- Toxicity Study

0. 1500. 5000 or 15.000 NOAEL= 5000 ppm (equivalent to 7800 mglkglday). Inhalation- Sprague- ppm (eq uiv al e nt to 2340, Daw le y R at 7 800 and 3 1 2 00 m glkgl day) LOAEL= 15000 ppm (eq uivalent to 31200 m glkgld ay) base d on in crease d monocytes. potassi um and in creased incidence of multi focal mononuclear cell i n filtrates in the heart. 90-Day Toxicity Study 0 , 2000 and I0000 ppm NOAEL = I 0000 ppm {approximate l y 15600 m glkglday wi th toxicogenomic (equ ivalent to 3120 and human equivalent dose). assessment of cancer potential- B6C3 F I fema l e 15600 mglkglday). LOAEL was not established. mice and F344 mal e rat- Cla ss ified as non -carcinogen i c. Inhalation Developme nt al toxicity0, 1 50 0, 5000 and 1 5000 M aternal NOAEL = 1500 0 ppm (eq uival e nt to 23400 Wi star r at
- Inh alati on ppm (equivalent to 2340. m g/

k

glday). 7800 and 23400 Maternal LOAEL was not established. mglkglday). Developmental NOAEL = 15000 ppm (eq uiv al en t to 23400 mglkglday). Developmental LOA EL \ vas no t establi shed.

14

### Tab le 3. Toxicology Profile for T r an s -1 , 1, 1 , 3-tet ra fl uoropropene Study Type Doses Res u lts
Deve l op mental tox ici ty 0, 1500, 5000 and 15000 Mat e rn al NO AEL = 15000 ppm (equ ivalent to 31200 (range-finding st udy) -New ppm (equivalent to 2340, mglkg/day). Zealand White rabbit

- lnJ1al at ion 7800 and 23400 Matern al L OAEL was no t es tabli s h ed. m

g/

kg/day)

. Developmental OAEL = I 5000 ppm (equiva lent to 3 1200 m

glkg/day). Developmental LOAEL was not es t ab li shed. Developmental toxicity4,000, I 0000 or 15000 Matern al and D eve lopme nt al NOAELs = 15000 ppm New Zealand White rabbit ppm ( eq uiv al ent to 6240. (equ ivalent to 23400 m g/

kg/ day)

. -Inhalation 15600 and 23400 Maternal and Developmenta l LOAELs were not mglkg/ day) establi s h ed. Am es Test

- Ga s exposure 0 or 50000 ppm with and Negative withou t S9 (ap proximat e l

y 7800 m g/

k

glday). Ame s Tes t- Gas ex pos ure 0, I%, 2%, 2. 5% , I0%
. Negative 20% and 50% (approximately 0

. 10000 , 20000,25000, 100000, 20000 0 , and 500000 ppm) with and withou t S9 Metabolism -M ale S prag ue- 0 o r 2, 000 ; I0 , 000 ; o r HF0-1234ze (CAS# 1 645-83

- 6) adm ini ste r e d via inhalation Dawl ey Rat-Inh alation 50.000 ppm (approximatel y to mal e rat s is rapidly absorbe d. metaboliz ed and excreted equiva l e nt to 3 1 20, 15600 (the majority within 18 hrs). The urine was the major route and 7 8000 m g/

k

g/

day). o f excretion. The major m etabolite was S-(333 -tri tluoro

trans-propenyl)-mercaptolactic acid. Other identified metabolites were S

- (3

. 3 , 3 -tritluoro-transpropenyf)

- Lcys teine, N

- acety l-S

-(3 ,3 .3 -tritl uoro-tran s-pro pe n y l)- Lcyste in e and 3 ,3.3 -tritluoropropionic acid. Metabolism

- Male B 6C3 F 1 0 or 50,000 ppm 

### HF O- I234ze (CAS# 1645-83-6) adminis tered via mice -Inhalati on (app roximate l y equiva l ent in hala ti o n to mal e rat s is r ap idl y abso rbed , m e taboli ze d and to 78000 m g/kg/ day). ex creted (th e majority within 18 hrs). The urine was the major route of excre ti on. The major metabolite was a pre sum ed am in o ac id co nju gate of3 ,3, 3-tritluoropropionic ac id

. Other identified metabolite s were S

- (3.3,3 -tr itluoro

transpropenyl)- L-cysteine , N-acetyl-S

-(3

. 3,3 -tritlu o ro trans-propen y l)-L-cys teine and 3,3,3- tritlu o r op r opion i c ac id

. Acute Cardiac 0, 20, 000 , 60,000 o r NOAEL = 120,000 ppm (approximately 187 ,200 Se ns iti zation-Dog 1 20.00 0 ppm m glkg/day). (ap proximate l y equivalent LOAEL was not established. to 3 1200, 93600 and 18 7200 mglkgl day).

154 . T o xi c i ty E ndp o int Selection The available toxicity studies indicate that trans- I , I , l , 3-tetrafluoropropene has a very low overall toxicity

. The lowest NOAEL in the database was 5000 ppm (ap proximatel y 7800 mg/kg/day human equivalent dose) observed in a 13 week toxicity study in rats via the inhalation route of exposure. Since s igns of tox icity were not observed at well above the limit dose an endpoint of co nc ern for risk assessment purposes was not identified. Therefore , since no endpoint of concern was identified for the acute and chronic dietary exposure assessment and short and interme diate dermal a nd inh alation exposu re , a qualitative ri sk assessment for trans- I , l, I , 3-tetrafluoropropene was conducted. 

### 5. Specia l Co ns iderations for Infants and Chi ldren As part of its qualitative assessment , the Agency did not use safety factors for assessing risk. and no additional safety factor is needed for assessi ng ri sk to in fan ts and children

. Based on the lack of toxicity of trans l-3 , 3 , 3-tetrafluorop ropene in the available studies , EPA has concluded that there are no toxicological endpoints of concern for the U.S. population , including in fants and children.


### 6. Ex po s ure Assess ment Dietary Exposure: In evalu ating dietary exposure to trans 1-3 , 3 , 3-tetrafluoropropene , EPA considered exposure under the petitioned for exemptions from the requirement of a tolerance. S inc e no endpoi nt of concern was identifi ed for the acute and ch ronic dietary exposure assessment and s hort and intermediate dermal and inhalation exposure, a quantitative risk assessment for trans 1- 3, 3, 3-tetratluoropropen e is not necessary. Cance r. Trans 1-3, 3, 3-tetrafluoropropene is not expected to be ca rcino genic based on it s lack of toxicity and the negative response for mutagenicity. Therefore , a cancer dietary exposure assessme nt was not performed.

Re s idential (No n-O ccupat ional) and Occupational Exposure: The tenn " re s id ential exposure" is used in this document to refer to non- occupational. nondietary exposure (e.g., for lawn and garden pest control , indoor pest control , termiticides , and flea and tick contro l on pets). Trans 1-3 , 3, 3-tetratluoropropene may be u sed in inert in gredients in products that are registered for specific uses that may result in residential exposure. However. since an endpoint of concern was not identified, a qual itative assessment was co n ducted.


### 7. Occupation a l Exposure/Risk Pathway

16Occupational exposure was qualitative ly assessed si nce an endpoint of concern was not identified for trans 1

- 3 , 3, 3

- tetrafluoropropene. · 8. C umul ative Ex po s ure: Section 408(b)(2)( D )(v) of FFDCA requi res that , when cons idering whether to establish , modif y, or revoke a tolerance , the E PA co n sider "ava il ab l e in fo rm atio n " co ncerning the cumu l ative effects of a particular pesticide's residues and "othe r substances that have a common mec hani sm of toxic ity." Unlik e other pesticides for which EPA has fo ll owed a cumulati ve risk approach based o n a common mec hani s m of tox ici ty, E PA has n ot made a common mechanism of toxic ity findi ng as to trans 1- 3, 3, 3-tetrafluoropropene and any ot her substances and , this material does not appear to produce a toxic metabolit e produced by other subs tan ces. For th e purposes ofthis tolerance ac ti on , therefore , EPA has not assumed that trans 1- 3, 3. 3

- tetrafluoropropene have a common mechanism of toxicit y with other s ubstances. Fo r in fo rmati o n rega rdin g E PA' s effo rts to determine which chemicals have a co mm o n mechanism of tox icity and to evaluate the cumulative effects of suc h chemicals , see th e policy s tatem ents rel eased by EPA's Office of Pesticide Programs concernin g common mechanism detenninations and procedures for cumulating effe cts fro m s ubstance s found to have a common mec hani sm on EPA's webs ite at http: //www.epa.gov/pesticides/ cumulative /

. 9. Environmental Fate Env ironmental fate data were reproduced from toxicity stud ies sub mitted by The Acta Group, L.L.C., on behalf of Honeywell S pe cia lty Materials N l C4

. The biodegradab ili ty of trans 1-3 , 3, 3-tetrafluoropropene by microorganisms was evaluated accord in g to the Close d Bottle Test. Trans 1- 3 , 3, 3-tetrafluo roprope ne (2. 73 mg theoretica l oxyge n demand (ThO.I- 1)) was cu ltivated with mineral medium inoculated with sludge filtrate (fo r 28 days (sealed and standin g) in darkness. DO was calculated on days 7 , 14 , 2 1 and 28; and BOD was calcul ated on days 7 and 28. Trans 1-3 , 3 , 3 -tetrafluoropropene was inhibitory to the in oculum at 2

. 8 mg /1 · 1 • The authors concluded that trans 1

- 3, 3, 3 -te tratluoroprop e ne was not biodegraded by mi croo rgani sms under the conditions of the s tudy (M RJD 48649506). In a seco nd s tudy, th e biode g r adabil ity of trans 1- 3, 3, 3-tetratlu orop ropene by microorganisms was evaluated accord in g to the Clo se d Bottle Test. Trans 1-3 , 3 , 3- tetrafluoropropene (7.39 mg/L) was cultivated with mineral medium inoculate d wi th sludge filtrate (fo r 2 8 days (sealed and s tandin g) in d arkne ss. Di sso lv e d oxygen (DO) and bioche mical oxygen demand (BOD ) were ca lculated o n days 7, 1 4 ,2 1 and 28. Trans 1

- 3, 3 , 3

- tetratluoropropene was not biodeg raded by microorganisms under the co nditi o n s of this study ( MRJD 48649504).

l 0. Eco toxicity

17These data were reproduced from toxicity studies submitted by The Acta Group , L.L.C., on behalf of Honeywell Specialty Materia ls N IC4. Aquatic Effects 

### Acute Toxicity to invertebrates (Daphnia magna): Test media was exposed to CAS # 1645- 83-6 for 4, 7.5, 1 5 , 30 and 60 minutes. The test consisted of four airtight closed vessels per co nc e ntration each vessel containing 5 daphnids. Samples for analysis of actual exposure concentrations were taken at the start and the end of the 48-hour test. C hemical analysis showed initial conce ntrati ons of90 , 200 and 400 mg/1 

### in the solutions exposed to trans 1-3 , 3, 3- tetratluoropropene for 15 , 30 and 60 minutes , respective ly. The geometric mean concentrations we re 50 , 160 and 350 m g/ 1, re spectively. No more than I 0% immobilization was recorded at measured concentrations of up to 160 mg/1, while 45 % was recorded at the highe st concentration of 350 m g/ I after 48 hours of exposure. The study met the acceptability criteria prescribed by the protocol and was considered valid. The 48h-ECso for Daphnia magna ex po sed to CAS # 1645-83-6 was > 160 mg/1, the no observed effect concentration CAS # 1 645-83-6 can be classified as not harmful for crustaceans (Bogers , 2006; MRID 48649507). 

### Acute Toxicity to algae: Exponentially growing algal cultures were exposed to solutions with an initial concentration of 480 mg/1 of CAS # 1 645-83 -6 for 72 hours under continuous illumination. Each test group consisted of 6 replicates, i.e. in airtight closed vessels with a screwcap holding a septum. The volume ratio of solution and vessel was 3:4 and the initial cell density was I x 104 cells / mi. Samples for analysis were taken from all test concentrations and the control at the start and at the end of the test. At the end of the 72-hour test period, the concentrations of CAS # 1645-8 3-6 varied markedly among the different rep li cates (41 to 111 mg/1). Based on these resu lt s. the overall average exposure concentration was 170 mg/1 , whi le the maximum average concentration was 230 mg/1. B ased on the area under the growth curves, total cell growth was inhibited by > I 0% but < 50 %. A significant lower mean growth rate was recorded for the treatment control compared with the blank

- control for the 0-24h interval. Compared with the treatment cont ro l , the CAS # 1645-83-6 treated solutions reduced the growth rate by less than 10 %. The NOEC of CAS # 1645-83-6 for total cell growth of fresh water algae was < 170 mg/1 (NOEsC), while for growth rate it was 170 mg/1 (NOERC). The ECso of CAS# 1645-83-6 > 170 mg/1 for both total ce ll growth and growth rate, and CAS # 1645-83-6 can be classified as not harmful to fresh water algae ( Bogers. 2006; MR ID 48649509).
11. Env iro nm enta l Ju stice P otential areas of environmental justice concerns , to the extent possible , were considered in this human health risk assessment, in accordance with U
. S

. Executive Order 12898, "Fede ral
18Actions to Address Enviro nmental Justice in Minority Popul a tion s and Low- Income Popu lat io n s," http: //www.eh.doe.gov/ oepa/gu idance/ju s tice/eo l2898.pdf). As a part of every pesticide risk assessment, OPP co n s id e rs a large va ri ety of consumer subgroups acco rdin g to well-establ i shed proce dures. In line wi th OPP polic y, H E D estimates risks to population su b gro up s from pesticide expos ures that are based on patterns of that subgroup ' s food and wate r consumption , and activities in a nd around the hom e that invol ve pe sti c ide u se in a resid e nti a l settin g. Exte n s ive data on food co n s umption pattems are compiled by the US DA und e r the Continuin g Survey of Foo d intake by Indi vidual s (CSF IJ ) and are u sed in pes ti cide risk assess ments fo r a ll r eg istered food uses of a pest icide. T hese data are anal yzed and c ategorized by s u bgroups based o n age , season of the year , ethnic group , and region of the country. Additionall y, OPP is ab le to assess dietary exposur e to s maller , spec ia li zed s ubgro up s and expos ure assessments are performed when conditions or circumstances warrant. When ever app rop ri ate, non-d ietary expos ure s based o n ho me use of pesticide product s and assoc iated ri sks for adult app li cator s and for toddlers, youths. and ad ult s ente rin g o r playing on treated areas postapplication are eval u ated. Furth e r co n s iderations are curre ntl y in developme nt as OPP ha s committed resources and expertise to the deve lopme nt of specialized software and models that consider exposure to bystanders and farm worke rs as well as life sty le and traditional dietary patte m s a mon g specifi c s ub group s .


### 12. Ri s k C h a ra cte riza ti o n E P A re ce ived a petition ( PP# lE79 38) fro m The Acta Gro up , L. L.C. , 2000 Penns y l van ia Avenue , N .W ., Suite lOOW Wa s hi ngton , D. C. 2003 7 , on be ha lf of Honeywe ll S p ec ialty Materials N IC4 , 101 Co lumb ia Road, Morristown , NJ 07962-1053 requ estin g an exempti on f rom t he requirement of a tolerance for the u se of trans 1

- 3 , 3, 3-tetratluoropro pene (CAS Reg. No. 29 118- 24-9) as an in ert ingredient (propellant) up t o 30% in pesticide product s on all pre- and post-harvest food commodities under 40 CFR part 180.91 0; in pesticide products applied to animals , 40 C FR part 180. 930; and in p estic id e products u sed for food

- contact surface sanitizing solutions , 40 CF R part 180.940(a )

. E P A publi s hed the notice of fi li ng (NOF) for this pe tition in the Federa l Reg i s ter on April 4, 20 12 (77 F R 43566). No com ment s were r ece ived in respon se to this notice. Current ly. trans 1- 3, 3 , 3

- tetrafluoropropene i s reco mmended for approval as an aerosol propellant und e r th e Significant New A lte rn at ives P o li cy (SNA P) as an alte rn ative for ozone-dep leting s ub stances. Thi s r is k assessment evaluated the pote ntial human hea lth associated with th e inhalation exposure sce nario re s ultin g from the u se of trans 1-3 , 3 , 3 -te tr afluoro prop ene. In some of the studies the che mic al name was incorrect but was correctly identified by the alternate CAS # 1 645 -8 3-6. Therefore , in the following studies , trans 1- 3, 3, 3- tetratluoropropene was id e ntifi ed by the a lternate CAS # 1645-83-6 when the incorrect nam e was used. To xic ity s ummar i es of trans l -3 , 3 , 3 -te tra fluoroprop e ne were reproduced f ro m data s ubmitted by The Acta Group , L.L.C., on behalf of Honeywell Spec ialty M ate ri a ls N IC4. Tran s 1

- 3 , 3 , 3-tetrafluoroprope ne was admini stered v ia the inh a latio n route of exposure only in the se studies.
19Acute inhalati on toxicity was low for CAS # 1645-83-6 in rats and mice. It was not a dennal irritant in rabbit s. Trans 1-3 , 3, 3-tetratluoropropene did not cause any effec ts at doses up to 5000 ppm (approximatel y 7800 m g/kg/day human eq uivalent dose) in rat s and rabbit s via the inhalation route of exposure. It does n ot exhibit th e potential for teratogenicity , neurotoxicity , immunotoxicity, mutagenicity or carcinogenicity. Metabolism studies showed th at it was rapidly absorbed, metaboli ze d and excreted. Urine was th e major route of excretion. In rats , the major metabolite was S-(333-trifluoro-trans-propenyl)-mercaptolactic acid. In mice, the major metabolite was a presumed am in o acid conj ugate of 3 , 3,3-tritluoropropionic acid. Other identified m etaboli tes were S-(3 ,3 ,3 -tritl uoro-transpropenyl )- L-cysteine , N -acety l-S-(3 ,3 ,3- trifluoro-trans-p rop e ny l)-L-cy ste ine and 3 , 3,3-trifluoropropionic acid. Dietary , non-dietary and occupational exposures were qualitatively assessed since and en dpoint of concern was not id en tified. Trans 1-3 , 3 , 3-tetrafluoropropene is expected to persist in soil and sediment. Bioconcentration in aquatic organisms is moderate to high

. It is not expected to be toxic to aquatic organisms. Trans 1-3 , 3, 3-tetratluoropropene i s n ot biode graded by microorganisms in s lud ge . Potential areas of environmenta l justice concerns , to the extent possible, were considered in this hwnan health risk assessment, in accordance with U.S. Exec utive Order 128 98 , "Federal Actions to Address E nvironme ntal Ju s ti ce in Minority Popul at ions and Low-Income Populations," http: // www.eh.doe.gov/ oepa/guidance /justice / eo l2898.pdf. Taking into consideration all available information on trans l-3, 3 , 3- tetrafluoropropene. EPA concludes that there is a reasonable certainty that no harm w ill r esult to the general population or to infants and children from aggregate exposure to trans 1-3, 3 , 3- tetrafluoropropene. Therefore, the establishment of an exemption from tolerance under 40 CFR 180.910 , 180.930 and 180 .940(a) for residues of trans 1-3, 3 , 3-tet raflu oropropene w hen used as an inert ingredient (prope llant) at no more than 30 % by weight in the end-product formulation can be considered safe under sec tion 408 of the FFD CA.

20

### REFERENCES Bogers, M. (2006) Pr e liminar y Experiment for Development of a Method for Optimal Mainte nanc e of Test Co ncentration in Aqueous Media as Use d in Aquatic Toxici t y Tests With XXXXX

. Study No. 6473 / 01. Unpubli s hed study prepared by TN O Quality of Life , Utrechtseweg 48 , 3700 A J Zeis t , Th e Netherlands. MRID 48649507

. Bo ge rs , M. (2006) Acu t e toxicit y study in Daphnia m agna With XXXXX. Study No. 6473 / 03. Unpublis hed study p repare d by TNO Quality of Life, Utrechtseweg 48 , 3700 AJ Zeist, Th e Nether lands. MRID 48649508. B ogers , M. (2006) Fresh Water A lgal Growth Inhibiti on Test With XXXXX. Study No. 6473 / 02. Unpublished stu dy prepared by TNO Quality o f Life, Utr ec htsew eg 48 , 3700 AJ Ze ist , Th e Nethe rland s. MRID 48649509. Cremers. R. and Hamwijk, C. (2007) Determination of the Ready Bi odegradabili ty of HF0- 12 34ze (CAS # 29118

- 24-9) in a Closed Bo ttl e Test. Study No. 7242

. Unpub li s hed study prepared by TNO Qu ali ty of L if e , Utrechtseweg 48, 3700 AJ Zeist , The Netherland s. MR ID 4864 950 6. DiD onato , L. (2010) Primary Dermal Irritat io n/Co rro sion in Rabbits. Pr oject Number : 6473 / 03 444882

. Unpub li shed stu dy prepared by MB Re sea rch Laboratories. MRlD 486495 I 0

. Dosik , 

### J. (201 0) Repe ated In sult Patch S tud y. Project Numbe r: 6473 / 03 444882. Unp ubli s hed study prepared by TKL Res earc h , Inc. M RID 4864951 I. EPA. (201 0) Significant New Al te rnati ves Poli cy Pro gram Aeroso ls Sector. Ri sk Sc reen on Subst itues for CFC-1 L HCFC-22, and HCFC

- 142b as Ae rosol Propellant s. Subst itute: HF0- 1234ze. EPA. (2012) Health Effects Division S tandard Operatin g Procedures for Residential Pe stic id e Exposure Assessment. Fleeman, T. (2007) An Inhal ation Ran ge-fi ndin g Prenatal De ve lopme nt al Inha lation Toxicity Study of (Ine rt Ingredient) in Rabbits. Project Nu mber: 6473 / 03 444882. Unpubli s hed study prepared by WIL Research Laboratories. Inc. MRI D 486495 14. Jacob y, 

### H. (2012). Re: Petition Number 1E79 38 Tolerance Exemption P et it ion f o r a New Food Use Inert In gred ient: trans 1- 3. 3, 3-tetrafluoropro-1

- ene , CASRN: 29 1 18-24-9

- Submission of Additional Information R ega rdin g Pote ntial Residues in Food/Feed. J uly 9 , 20 1 2. Ho ffman , G. (2004) An Ac ute (4 -H our ) I nhalation Ran ge Findin g Study in the Mouse Via Whole Body Exposure

. Proj ect Numbe r: 6473 / 03 444882. Unp ubli s hed study prepared by Huntingdon Life Sciences. 55p. M RID 486495 1 2.

21Hoffman , G. (20 I 0) (In ert In g redie nt): Embr yo -fetal Toxici ty Study in Rabbit Via Whole Body Inhalation Exposure (GLP). Project Number: 09/4350. Unpublished study prepared by Huntingdon Lif e Sciences

. MRID 48649519. Hori, K. (2008) Measurement of 1-octanol / water partition coef fici en t for XXXXX (t ran s)( HPL C method). Stud y No. 8 3068

. U np ubli s hed s tudy prepar ed Kurume Labo rator y , Chem icals Evaluat ion and Research In stitute, 2 -7 , 3-chome , Miyanojin , Kurume-shi , Fukuo ka 839

- 080 1 , J apan . MRJD 4864950 3

. K ayas him a , T. (200 8 ) Biodegradation Study of XXXXX (trans) by Microorganisms. Study No

. 83068. Unpublished s tudy prep are d Kurume Labo ratory , Chemicals Evaluat ion and Re search Institute , 2-7 , 3-chome , Miyanojin , Kurume-shi , Fukuoka 839-0801 , Jap an. MR ID 48649504. Kitching , J. (1997) (CAS # 29 11 8

- 24- 9) : Bacterial Mu t ati on Assay. Project Number: MA/252 A/ 93 /46 96008/MA/252A ALS/129 / 96 1626. Unpublished s tudy prepared by Huntin gdo n Lif e Sc i ences , Ltd

. 62p. MRJD 48649521. Muijser, H. (2006) Sub-chronic (2

- Week) Inhalation Tox icity Study with (In ert Ingre di en t ) in Rats. Pr oject Number: 6473 / 03 444882. Unpublished stu d y p repared by TNO Quality of Life

. MRID 48649515. Muijser , H. ; Junker , K. (2006 ) Sub

- Chronic (4-Week) Inhalation Toxic ity Study , In c ludin g Unsc hed ul ed D NA Synthesis and Micronuc le u s Te s t, with ( I nert Ing redi e nt) in Rat s. Proj ec t N umber: 6747

. Unp ubli s he d study prepared by TN O Quality of Li fe. MRID 48649516. Muijser, H. (2006) Sub-chronic (13- Week) Inh alation Study wi th (In ert In g red ient ) in Rats. Project Number: 7383. Unpublished study prepared by TNO Qualit y of Life. M RID 48649517. Noguc hi , T. (2009) Mutagenicity Te s t of (Inert In gred ie nt) Using Microorganisms [ Rever s emutation Assay of ( Inert Ingr e di e nt) Using Microo rgan isms]. Pr ojec t Number : 630 I. U npubli s he d study prep a re d by Japan Bioas say Res earch Center. 35p. MRID 4864 9522. Tege lenb osch-Shoute n , M. (2007) Pr e nata l Developmental Inhalati o n Toxi c it y Study w ith ( Inert In gre di e nt) in Ra ts . Pro ject Number: 7 384. Unpub li s hed study prepared by TN O Quality of Life. M RID 48649518. Tho m as , R. (2007) T oxicogenomic Assess men t of th e Carcinogen ic Potential of (Inert In g redie nt). Pr ojec t N umb er: 06014. U npubli s h e d s tud y prepared by C TTT Ce nters fo r H ea lth Researc h (now called the Hamn er In st itues for Health Sciences). MRID 48649520. Schuster, P. ; B erte nnann , R. ; Ru sc h , G. et al. (2 009) Biotran s fonnation of trans-1

. I , I , 3- tetrafluoropropene (HF 0-1234ze). Tox icology and Applied Ph annaco logy 239: 215-223. M RJ D 48649524.



### 22Spruit, W
. , Mak, W. , and Schouten, A. (2006) Determination of some Ph ysico-Chemica l Properties of:XXXXX. Study No. TNO DV2 2006-031 / 01.03-02. TNO Defence. Security and Safety , Lange Keilweg 137 , P.O. Box 45, 2280 AA Rij sw ijk , The Netherlands. Weinberg , J. (2 004) Acute Cardiac Sensitization Study of HF0-1234ze and HFO 1234 yf in Do gs: Final Report. Project Number: 447008. Unp ubli shed study prepared by WIL Research Laboratories, fnc. 105p. MRlD 48649523.

23Appendix.
The toxicological endpoint or point of departure was identified from an inhalation exposure study. The endpoint was identified as being 5000 ppm/ day. In order for the Agency to complete a ri sk assessment , that e ndpoint must be converted to a dose in mg/kg bw / day for use in risk calculation. The following convention is utili z ed by the Health Effects Division , Office of Pesticide ProgramsfUSEPA to convert endpoints expressed in parts per million to an expression in mglkg bw/day in humans based on 24 hour exposure. Part s per million (ppm) conversion: Trans 1-3 , 3, 3-tetrafluoropro-1-ene molecular weight = 114 g/mol Conversion factor for gases and vapo rs: ppm to mg/m3 at 25 ° C is 24.25 ppm x MW / 24.45=23,300 mg/m 3 5000 ml / m 3 x 114 / 24 , 45 Human Equiva lent Do se: mg/kg bw / day 

### = mg/m 3 x respiratory volume during exposure / exposure timex body weight (kg bw) Thus , mglkg bw / day = 23 , 300 mg/m 3

_ x 20m3 / day x 1 / 60 kg bw= 7800 mg/ kg bw / day

24